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Sustained virological response from interferon-based hepatitis C regimens is associated with reduced risk of extrahepatic manifestations

  • Carmine Rossi
    Affiliations
    British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada

    Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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  • Dahn Jeong
    Affiliations
    British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada

    School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
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  • Stanley Wong
    Affiliations
    British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada
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  • Geoffrey McKee
    Affiliations
    British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada

    School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
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  • Zahid Ahmad Butt
    Affiliations
    British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada

    School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
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  • Jane Buxton
    Affiliations
    British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada

    School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
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  • Jason Wong
    Affiliations
    British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada

    School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
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  • Maryam Darvishian
    Affiliations
    British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada

    School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
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  • Sofia Bartlett
    Affiliations
    British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada

    Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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  • Hasina Samji
    Affiliations
    British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada
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  • Amanda Yu
    Affiliations
    British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada
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  • Mawuena Binka
    Affiliations
    British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada

    Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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  • Maria Alvarez
    Affiliations
    British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada
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  • Prince Asumadu Adu
    Affiliations
    British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada

    School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
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  • Mark Tyndall
    Affiliations
    British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada

    School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
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  • Mel Krajden
    Affiliations
    British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada

    Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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  • Naveed Zafar Janjua
    Correspondence
    Corresponding author. Address: Clinical Prevention Services, BC Centre for Disease Control, 655 West 12th Avenue, Vancouver, BC V5Z 4R4, Canada. Tel.: +1 604 707 2514; fax: +1 604 707 2401.
    Affiliations
    British Columbia Centre for Disease Control, Vancouver, British Columbia, Canada

    School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
    Search for articles by this author
  • for the BC Hepatitis Testers Cohort Team
Published:August 06, 2019DOI:https://doi.org/10.1016/j.jhep.2019.07.021

      Highlights

      • Chronic HCV is associated with many extrahepatic manifestations (EHMs).
      • Generalizable population-level estimates of the impact of cure on EHMs are lacking.
      • SVR was associated with a significant reduction in the risk of several EHMs.
      • Reduction in incidence ranged from 18% (anxiety disorders) to 47% (kidney disease).

      Background & Aims

      HCV infection is associated with several extrahepatic manifestations (EHMs). We evaluated the impact of sustained virological response (SVR) on the risk of 7 EHMs that contribute to the burden of extrahepatic disease: type 2 diabetes mellitus, chronic kidney disease or end-stage renal disease, stroke, ischemic heart disease, major adverse cardiac events, mood and anxiety disorders, and rheumatoid arthritis.

      Methods

      A longitudinal cohort study was conducted using data from the British Columbia Hepatitis Testers Cohort, which included ~1.3 million individuals screened for HCV. We identified all HCV-infected individuals who were treated with interferon-based therapies between 1999 and 2014. SVR was defined as a negative HCV RNA test ≥24 weeks post-treatment or after end-of-treatment, if unavailable. We computed adjusted subdistribution hazard ratios (asHR) for the effect of SVR on each EHM using competing risk proportional hazard models. Subgroup analyses by birth cohort, sex, injection drug exposure and genotype were also performed.

      Results

      Overall, 10,264 HCV-infected individuals were treated with interferon, of whom 6,023 (59%) achieved SVR. Compared to those that failed treatment, EHM risk was significantly reduced among patients with SVR for type 2 diabetes mellitus (asHR 0.65; 95% CI 0.55–0.77), chronic kidney disease or end-stage renal disease (asHR 0.53; 95% CI 0.43–0.65), ischemic or hemorrhagic stroke (asHR 0.73; 95% CI 0.49–1.09), and mood and anxiety disorders (asHR 0.82; 95% CI 0.71–0.95), but not for ischemic heart disease (asHR 1.23; 95% CI 1.03–1.47), major adverse cardiac events (asHR 0.93; 95% CI 0.79–1.11) or rheumatoid arthritis (asHR 1.09; 95% CI 0.73–1.64).

      Conclusions

      SVR was associated with a reduction in the risk of several EHMs. Increased uptake of antiviral therapy may reduce the growing burden of EHMs in this population.

      Lay summary

      We estimated the rates of chronic comorbidities other than liver disease between those who were cured and those who failed treatment for hepatitis C virus (HCV) infection. Our findings showed that the rates of these non-liver diseases were largely reduced for those who were cured with interferon-based treatments. Early HCV treatments could provide many benefits in the prevention of various HCV complications beyond liver disease.

      Graphical abstract

      Keywords

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      References

      Author names in bold designated shared co-first authorship

        • Polaris Observatory HCV Collaborators
        Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study.
        LancetGastroenterol Hepatol. 2017; 2: 161-176
        • Negro F.
        • Forton D.
        • Craxi A.
        • Sulkowski M.S.
        • Feld J.J.
        • Manns M.P.
        Extrahepatic morbidity and mortality of chronic hepatitis C.
        Gastroenterology. 2015; 149: 1345-1360
        • Younossi Z.
        • Park H.
        • Henry L.
        • Adeyemi A.
        • Stepanova M.
        Extrahepatic manifestations of hepatitis C: A meta-analysis of prevalence, quality of life, and economic burden.
        Gastroenterology. 2016; 150: 1599-1608
        • Cacoub P.
        • Comarmond C.
        • Domont F.
        • Savey L.
        • Desbois A.C.
        • Saadoun D.
        Extrahepatic manifestations of chronic hepatitis C virus infection.
        Ther Adv Infect Dis. 2016; 3: 3-14
        • Younossi Z.M.
        • Stepanova M.
        • Nader F.
        • Younossi Z.
        • Elsheikh E.
        Associations of chronic hepatitis C with metabolic and cardiac outcomes.
        Aliment Pharmacol Ther. 2013; 37: 647-652
        • Petta S.
        • Maida M.
        • Macaluso F.S.
        • Barbara M.
        • Licata A.
        • Craxi A.
        • et al.
        Hepatitis C virus infection is associated with increased cardiovascular mortality: a meta-analysis of observational studies.
        Gastroenterology. 2016; 150 (145–155 e144; quiz e115-146)
        • Park H.
        • Chen C.
        • Wang W.
        • Henry L.
        • Cook R.L.
        • Nelson D.R.
        Chronic hepatitis C virus (HCV) increases the risk of chronic kidney disease (CKD) while effective HCV treatment decreases the incidence of CKD.
        Hepatology. 2018; 67: 492-504
        • Cacoub P.
        • Nahon P.
        • Layese R.
        • Blaise L.
        • Desbois A.C.
        • Bourcier V.
        • et al.
        Prognostic value of viral eradication for major adverse cardiovascular events in hepatitis C cirrhotic patients.
        Am Heart J. 2018; 198: 4-17
        • Pol S.
        • Vallet-Pichard A.
        • Hermine O.
        Extrahepatic cancers and chronic HCV infection.
        Nat Rev Gastroenterol Hepatol. 2018; 15: 283-290
        • Younossi Z.M.
        • Tanaka A.
        • Eguchi Y.
        • Lim Y.S.
        • Yu M.L.
        • Kawada N.
        • et al.
        The impact of hepatitis C virus outside the liver: evidence from Asia.
        Liver Int. 2017; 37: 159-172
        • Cacoub P.
        • Buggisch P.
        • Carrion J.A.
        • Cooke G.S.
        • Zignego A.L.
        • Beckerman R.
        • et al.
        Direct medical costs associated with the extrahepatic manifestations of hepatitis C infection in Europe.
        J Viral Hepat. 2018; 25: 811-817
        • Tong X.
        • Spradling P.R.
        Increase in nonhepatic diagnoses among persons with hepatitis C hospitalized for any cause, United States, 2004–2011.
        J Viral Hepat. 2015; 22: 906-913
        • Katrak S.
        • Park L.P.
        • Woods C.
        • Muir A.
        • Hicks C.
        • Naggie S.
        Patterns of healthcare utilization among veterans infected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) and coinfected with HIV/HCV: unique burdens of disease.
        Open Forum Infect Dis. 2016; 3: ofw173
        • Simmons B.
        • Saleem J.
        • Heath K.
        • Cooke G.S.
        • Hill A.
        Long-term treatment outcomes of patients infected with hepatitis C virus: a systematic review and meta-analysis of the survival benefit of achieving a sustained virological response.
        Clinical Infect Dis. 2015; 61: 730-740
        • Cacoub P
        • Desbois AC
        • Comarmond C
        • Saadoun D
        Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis.
        Gut. 2018; 67: 2025-2034
        • Arase Y.
        • Suzuki F.
        • Suzuki Y.
        • Akuta N.
        • Kobayashi M.
        • Kawamura Y.
        • et al.
        Sustained virological response reduces incidence of onset of type 2 diabetes in chronic hepatitis C.
        Hepatology. 2009; 49: 739-744
        • Arase Y.
        • Kobayashi M.
        • Kawamura Y.
        • Suzuki F.
        • Suzuki Y.
        • Akuta N.
        • et al.
        Impact of virus clearance for the development of hemorrhagic stroke in chronic hepatitis C.
        J Med Virol. 2014; 86: 169-175
        • Hsu Y.C.
        • Ho H.J.
        • Huang Y.T.
        • Wang H.H.
        • Wu M.S.
        • Lin J.T.
        • et al.
        Association between antiviral treatment and extrahepatic outcomes in patients with hepatitis C virus infection.
        Gut. 2015; 64: 495-503
        • Arase Y.
        • Suzuki F.
        • Kawamura Y.
        • Suzuki Y.
        • Kobayashi M.
        • Matsumoto N.
        • et al.
        Development rate of chronic kidney disease in hepatitis C virus patients with advanced fibrosis after interferon therapy.
        Hepatol Res. 2011; 41: 946-954
        • Thrift A.P.
        • El-Serag H.B.
        • Kanwal F.
        Global epidemiology and burden of HCV infection and HCV-related disease.
        Nat Rev Gastroenterol Hepatol. 2017; 14: 122-132
        • Butt A.A.
        • Yan P.
        • Aslam S.
        • Shaikh O.S.
        • Abou-Samra A.B.
        Hepatitis C virus treatment with directly acting agents reduces the risk of incident diabetes – results from ERCHIVES.
        Clin Infect Dis. 2019;
        • Butt A.A.
        • Yan P.
        • Shuaib A.
        • Abou-Samra A.B.
        • Shaikh O.S.
        • Freiberg M.S.
        Direct-acting antiviral therapy for HCV infection is associated with a reduced risk of cardiovascular disease events.
        Gastroenterology. 2019; 156 (987–996 e988)
        • El-Serag H.B.
        • Christie I.C.
        • Puenpatom A.
        • Castillo D.
        • Kanwal F.
        • Kramer J.R.
        The effects of sustained virological response to direct-acting anti-viral therapy on the risk of extrahepatic manifestations of hepatitis C infection.
        Aliment Pharmacol Ther. 2019; 49: 1442-1447
        • Li J.
        • Zhang T.
        • Gordon S.C.
        • Rupp L.B.
        • Trudeau S.
        • Holmberg S.D.
        • et al.
        Impact of sustained virologic response on risk of type 2 diabetes among hepatitis C patients in the United States.
        J Viral Hepat. 2018; 25: 952-958
        • Mahale P.
        • Engels E.A.
        • Li R.
        • Torres H.A.
        • Hwang L.Y.
        • Brown E.L.
        • et al.
        The effect of sustained virological response on the risk of extrahepatic manifestations of hepatitis C virus infection.
        Gut. 2018; 67: 553-561
        • Berenguer J.
        • Rodriguez-Castellano E.
        • Carrero A.
        • Von Wichmann M.A.
        • Montero M.
        • Galindo M.J.
        • et al.
        Eradication of hepatitis C virus and non-liver-related non-acquired immune deficiency syndrome-related events in human immunodeficiency virus/hepatitis C virus coinfection.
        Hepatology. 2017; 66: 344-356
        • Nahon P.
        • Bourcier V.
        • Layese R.
        • Audureau E.
        • Cagnot C.
        • Marcellin P.
        • et al.
        Eradication of hepatitis C virus infection in patients with cirrhosis reduces risk of liver and non-liver complications.
        Gastroenterology. 2017; 152e142
        • Negro F
        Expanded benefits of curing the extrahepatic manifestations of HCV infection.
        Gut. 2018; 67: 1917-1919
        • Janjua N.Z.
        • Kuo M.
        • Chong M.
        • Yu A.
        • Alvarez M.
        • Cook D.
        • et al.
        Assessing hepatitis C burden and treatment effectiveness through the british columbia hepatitis testers cohort (BC-HTC): design and characteristics of linked and unlinked participants.
        PloS One. 2016; 11e0150176
        • Janjua N.
        • Chong M.
        • Kuo M.
        • Woods R.
        • Wong J.
        • Yoshida E.M.
        • et al.
        Long-term effect of sustained virological response on hepatocellular carcinoma in patients with hepatitis C in Canada.
        J Hepatol. 2017; 66: 504-513
        • Gray R.J.
        A class of K-sample tests for comparing the cumulative incidence of a competing risk.
        Ann Stat. 1988; 16: 1141-1154
        • Grambsch P.
        • Therneau T.M.
        Proportional hazards tests and diagnostics based on weighted residuals.
        Biometrika. 1994; 81: 515-526
        • Lee M.H.
        • Yang H.I.
        • Lu S.N.
        • Jen C.L.
        • You S.L.
        • Wang L.Y.
        • et al.
        Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study.
        J Infect Dis. 2012; 206: 469-477
        • van der Meer A.J.
        • Berenguer M.
        Reversion of disease manifestations after HCV eradication.
        J Hepatol. 2016; 65: S95-S108
        • White D.L.
        • Ratziu V.
        • El-Serag H.B.
        Hepatitis C infection and risk of diabetes: a systematic review and meta-analysis.
        J Hepatol. 2008; 49: 831-844
        • Lin Y.J.
        • Shaw T.G.
        • Yang H.I.
        • Lu S.N.
        • Jen C.L.
        • Wang L.Y.
        • et al.
        Chronic hepatitis C virus infection and the risk for diabetes: a community-based prospective study.
        Liver Int. 2017; 37: 179-186
        • Ruhl C.E.
        • Menke A.
        • Cowie C.C.
        • Everhart J.E.
        Relationship of hepatitis C virus infection with diabetes in the U.S. population.
        Hepatology. 2014; 60: 1139-1149
        • Gastaldi G.
        • Goossens N.
        • Clement S.
        • Negro F.
        Current level of evidence on causal association between hepatitis C virus and type 2 diabetes: a review.
        J Adv Res. 2017; 8: 149-159
        • Cacoub P.
        • Si Ahmed S.N.
        • Ferfar Y.
        • Pol S.
        • Thabut D.
        • Hezode C.
        • et al.
        Long-term efficacy of interferon-free antiviral treatment regimens in patients with hepatitis C virus-associated cryoglobulinemia vasculitis.
        Clin Gastroenterol Hepatol. 2019; 17: 518-526
        • Feng B.
        • Eknoyan G.
        • Guo Z.S.
        • Jadoul M.
        • Rao H.Y.
        • Zhang W.
        • et al.
        Effect of interferon-alpha-based antiviral therapy on hepatitis C virus-associated glomerulonephritis: a meta-analysis.
        Nephrol Dial Transplant. 2012; 27: 640-646
        • Hsu Y.C.
        • Lin J.T.
        • Ho H.J.
        • Kao Y.H.
        • Huang Y.T.
        • Hsiao N.W.
        • et al.
        Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic patients.
        Hepatology. 2014; 59: 1293-1302
        • Lee M.H.
        • Yang H.I.
        • Wang C.H.
        • Jen C.L.
        • Yeh S.H.
        • Liu C.J.
        • et al.
        Hepatitis C virus infection and increased risk of cerebrovascular disease.
        Stroke. 2010; 41: 2894-2900
        • Petta S.
        • Torres D.
        • Fazio G.
        • Camma C.
        • Cabibi D.
        • Di Marco V.
        • et al.
        Carotid atherosclerosis and chronic hepatitis C: a prospective study of risk associations.
        Hepatology. 2012; 55: 1317-1323
        • Adinolfi L.E.
        • Restivo L.
        • Zampino R.
        • Guerrera B.
        • Lonardo A.
        • Ruggiero L.
        • et al.
        Chronic HCV infection is a risk of atherosclerosis. Role of HCV and HCV-related steatosis.
        Atherosclerosis. 2012; 221: 496-502
        • Petta S.
        • Adinolfi L.E.
        • Fracanzani A.L.
        • Rini F.
        • Caldarella R.
        • Calvaruso V.
        • et al.
        Hepatitis C virus eradication by direct-acting antiviral agents improves carotid atherosclerosis in patients with severe liver fibrosis.
        J Hepatol. 2018; 69: 18-24
        • Hsu C.S.
        • Kao J.H.
        • Chao Y.C.
        • Lin H.H.
        • Fan Y.C.
        • Huang C.J.
        • et al.
        Interferon-based therapy reduces risk of stroke in chronic hepatitis C patients: a population-based cohort study in Taiwan.
        Aliment Pharmacol Ther. 2013; 38: 415-423
        • Janjua N.Z.
        • Yu A.
        • Kuo M.
        • Alvarez M.
        • Cook D.
        • Wong J.
        • et al.
        Twin epidemics of new and prevalent hepatitis C infections in Canada: BC Hepatitis Testers Cohort.
        BMC Infect Dis. 2016; 16: 334
        • Butt Z.A.
        • Shrestha N.
        • Wong S.
        • Kuo M.
        • Gesink D.
        • Gilbert M.
        • et al.
        A syndemic approach to assess the effect of substance use and social disparities on the evolution of HIV/HCV infections in British Columbia.
        PLoS One. 2017; 12e0183609
        • McKee G.
        • Butt Z.A.
        • Wong S.
        • Salway T.
        • Gilbert M.
        • Wong J.
        • et al.
        Syndemic characterization of HCV, HBV, and HIV co-infections in a large population based Cohort study.
        EClinicalMedicine. 2018; 4–5: 99-108
        • Butt Z.A.
        • Shrestha N.
        • Gesink D.
        • Murti M.
        • Buxton J.A.
        • Gilbert M.
        • et al.
        Effect of opioid-substitution therapy and mental health counseling on HIV risk among hepatitis C-infected individuals.
        Clin Epidemiol. 2018; 10: 1127-1145
        • Kraus M.R.
        • Schafer A.
        • Teuber G.
        • Porst H.
        • Sprinzl K.
        • Wollschlager S.
        • et al.
        Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C.
        Hepatology. 2013; 58: 497-504
        • Younossi Z.M.
        • Stepanova M.
        • Feld J.
        • Zeuzem S.
        • Sulkowski M.
        • Foster G.R.
        • et al.
        Sofosbuvir and velpatasvir combination improves patient-reported outcomes for patients with HCV infection, without or with compensated or decompensated cirrhosis.
        Clin Gastroenterol Hepatol. 2017; 15 (421–430 e426)